PROJECT 1 - IN (STROUD. PROJECT LEADER) Our goal is to understand the mechanism of HIV-1 integration mediated by integrase (IN), in the context of pre-integration complexes (PICs) that provide the targets for anti-IN drugs. The components of PICs, and interactions with viral and cellular proteins will be defined. Our plan builds on our 1.6 A resolution structure of the isolated core domain (IN52"210), our 2.6 A structure of the two-domain catalytic core plus Cterminal domain (IN52"288), and our exclusive ability to prepare homogeneous thiol-linked IN-DNA complexes. We will further analyze the crystal structure of IN without and with its natural substrate, the viral att site and target DNA, and use that knowledge to determine the mechanisms of anti-IN therapeutics.